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Online Journal of Microbiological Research
Academic Editor
Eman Mohamed
Article | Open Access | 10.31586/ojmr.2023.630

Drug-Receptor Interaction of Peptidic HIV-1 Protease: Intermolecular Interaction-III

Vishnu Kumar Sahu1, Neetu Chandra2, Anil Kumar Soni3,*, Pratibha Singh4 and Rajesh Kumar Singh1
1
Department of Chemistry, Maharani Lal Kunwari Post Graduate College, Tulsipur Road, Balrampur-271201(U.P.), (vishnukr_sahu@rediffmail.com@rediffmail.com) India
2
Department of Botany, Maharani Lal Kunwari Post Graduate College, Tulsipur Road, Balrampur-271201(U.P.), India
3
Department of Chemistry, Shia Post Graduate College, Sitapur Road, Lucknow-226020(U.P.), India
4
Department of Chemistry, K.S. Saket Post Graduate College, Ayodhya-224123 (U.P.), India
Received February 18, 2023
Revised August 1, 2023
Accepted September 13, 2023
Published September 26, 2023

Abstract

Recently, we have studied drug-receptor interaction of the peptidic HIV-1 protease inhibitors based on polar and hydrophobic interactions. We have also studied pharmacokinetics of these inhibitors based on Lipinski’s rule of five and its extended form. After that there was a need to study intermolecular interactions. From literatures, drug-receptor interaction involves hydrogen bonds between acceptor and donor sites of drug and its receptor. These donor acceptor sites must be more than four to be dominant. As single intermolecular H-bond is relatively weak and unlikely to support this type of interaction. It is also clear from literature that this interaction contribute to the alignment of reacting species in proper three-dimensional space in such a position that strong and effective polar or hydrophobic or both interaction occurs to form drug-receptor adduct or enzyme inhibitor complex as appropriate. The strength of H-bonds formed between drug and receptor was judged by bond lengths, bond angles and bond orders. As well as, its nature (strong, moderate or weak) and its number, too. Along with H-bonding, we have also studied Van der Walls i.e. non-bonding type interaction. These non-bonding interactions were studied using charge transfer from donor to acceptor and this results transfer of electron flux from donor molecule (drug/receptor) towards acceptor (receptor/ drug). Thus, lowering of energy of the system under investigation will occur. For this resulted interaction energy was also studied that very clearly explain feasibility of interactions. As we know that all above phenomena are molecular properties and do not cover involvement of orbitals. To cover this we have also studied drug-receptor interaction involving molecular orbital. It was HOMO of one reacting molecule (B) that donates electron pair, electron cloud or electron density to LUMO of another reacting molecule (A) that accepts or accommodates this electron pair, electron cloud or electron density. The quantity of the electron flux from HOMO to LUMO was judged by the value of ∆ELH. A lower value of this will support strong and effective drug-receptor interaction. Results of orbital based study have also been found to supports the results as abstracted from interaction energy.

1. Introduction

In our previous publications we have studied pharmacokinetics followed by drug-receptor interaction based on hydrophobic and polar effect [1, 2, 3]. Here, we have studied intermolecular interaction between drug and receptor’s amino acids that strengthen the formation of enzyme-inhibitor (EI) complexes [4]. In the mater of describing the stability of EI-complexes formed based on various factors among them one is intermolecular interaction [5]. This interaction also has same importance as the other bindings. This work is selective and covers both hydrogen bonding [6] and Van der Waals i.e. nonbonding type interaction [7, 8]. In H-bonding only intermolecular bonding is studied. From literatures, drug-receptor interaction involves hydrogen bonds between acceptor and donor sites of drug and its receptor. These donor acceptor sites must be more than four to be dominant. As single intermolecular H-bond is relatively weak and unlikely to support this type of interaction. It is also clear from literature that this interaction contribute to the alignment of reacting species in proper three-dimensional space in such a position that strong and effective polar or hydrophobic or both interaction occurs to form drug-receptor adduct or enzyme inhibitor complex as appropriate. The strength of H-bonds formed between drug and receptor was judged by bond lengths, bond angles and bond orders. As well as, its nature (strong, moderate or weak) and its number, too. Further, its nature and number is an important factor for controlling the interaction phenomenon and also affect the ADMET property of the drug [4, 9]. While, Van der Waals type interaction is based on (i) charge transfer (ΔN), (ii) energy lowering (ΔE), (iii) the interaction energy (ΔEint.) [10, 11, 12] and followed by (iv) change in energies of frontier orbitals (ΔELH) [13, 14]. Intermolecular interactions govern the formation of many systems of interest: Lewis acid-base complexes [15], pharmaceuticals-absorbers complexes [16] and protein-drug systems [17]. Our research group also studied 324 intermolecular interactions between metal halides and organic bases [18] and 150 interactions between metal-bicyclam complex and aspartic acid [17]. In these systems metal salts were present. But in this work, both parts of the system under investigation are organic molecules.

2. Materials and Methods

Here, fifty-one peptidic HIV-1-PRIs [1] and receptor proteins (scheme 1) are the study materials [1, 2, 3]. The sites of interaction on receptor proteins are amino acids. These are valine and isoleucine amino acids of binding site, and aspartic acid, threonine and glycine amino acids of catalytic site [20, 22]. For measurement of enzyme-inhibitor interaction, the molecular modelling and geometry optimization of all the compounds and concerned amino acids of receptor protein were computed with CAChe Pro software by applying semiempirical and opting parametric model 3 [23]. After optimizing all the chemical species and insuring that this represented a minimum energy structure. The energy of protonation is used to determine the correct locations of most favorable hydrogen bonds acceptor sites and results are tabulated in four tables respectively, Table 1(A to C) and 2. After that, we have calculated bond lengths, bond angles and bond orders of H-bonds formed between drug (inhibitor) and receptor (on protease enzyme). These calculated parameters are tabulated in twelve tables, Table 4A1 to 4A4 for first set; Table 4B1 to 4B4 for second set; and Table 4C1 to 4C4 for third set. The values of “∆N and ∆E”, “ΔEv, ΔEμ and ΔEint”, and “∆ELH” were obtained by solving the respective equation as described in section 3.2 using energy calculator developed by our research group. And the results are presented in Tables 6 to 8, respectively. For this, using absolute electronegativity (χ) [15], firstly each compound has been classified as acid or base with respect to each receptor amino acid and is presented in Table 5 and then respective equations were solved to get the required data.

3. Results and Discussion

For sake of simplicity this section has been divided into two different sections, one based on H-bonds and other on non-bonding.

3.1. H-Boding based study

It has been discussed already that HIV-1-PR is capable of forming multiple hydrogen bonds with the inhibitors. All protease inhibitors bind to the protease binding site pocket that has a considerable number of hydrophobic residues. The residues that make up these pockets are Val-32, Ile-47, Ile-50, and Ile-84 in each monomeric polypeptidic unit of the protease enzyme [19, 20, 21]. Out of fifty-one compounds listed in Table 1, the eighteen compounds (compound no. 1-18) have the parent skeleton of Figure 1 (first set that is A group), which has 25 sites. Out of remaining thirty-three, the seventeen compounds (compound no. 19-35) have the parent skeleton of Figure 2 (second set that is B group), which has 33 sites. While the remaining sixteen compounds (compound no. 36-51) have the parent skeleton of Figure 3 (third set that is C group), which has 29 sites. The number of hydrogen bond donors in each set of peptidic HIV-1-PRI was counted by counting the sum of NH and OH groups, while the number of hydrogen bond acceptors was counted by counting the sum of N and O atoms from their parent skeleton structure (Figure 1-3) [24, 25, 26]. A close look at the parent skeleton (Figure 1) of first set of peptidic HIV-1-PRI shows that it has five nitrogen and four oxygen atoms. Out of five N-atoms, one (site-8) acts as donor, while the rest (site-1, 4 and 8 to 14) act as both donor and acceptor. In case of oxygen atoms, the one at site-23 acts as both acceptor and donor, while the rest at site-13, 15 and 25 can only accept the hydrogen. Further, from ground-state properties of the individual compounds, we have predicted the hydrogen bond acceptor strength of acceptor site.

Figure 1
Parent skeleton along with reactive sites (compound no. 1-18, first set = group A)
Figure 2
Parent skeleton along with reactive sites of compound no. 19-35 (second set = group b)
Figure 3
Parent skeleton along with reactive sites of compound no. 36-51 (third set = group C)
Scheme 1
Hydrogen bonds acceptors and donors sites of amino acids of receptor protein (Reference 22).
Scheme 2
Geometry of a hydrogen bond. The distance H····O is typically between 2.8 and 3.2Ǻ and the angle N–H····O is most often larger than 150˚. The angle C=O····H has a much broader range; typical values are between 100 and 180˚. (Reference 25)

For this, we have evaluated energy of protonation of all these sites and are presented in Table 1 [27]. A reference to this table shows that the top four favorable hydrogen bond acceptor sites are O25, O15, O13 and N10, as these sites have higher energy of protonation. Parent skeleton (Figure 2) of second set shows that it has five oxygen and two nitrogen atoms. Out of five O-atoms, three (site-2, 23 and 32) act as acceptor, while the rest (site-31and 33) act as both donor and acceptor. In case of nitrogen atoms, both (site-4 and 10) act as both acceptor and donor. We have also evaluated energy of protonation of all these sites and are presented in Table 2. A reference to this table shows that the top four favorable hydrogen bond acceptors are O32, O23, O33 and N10, as these sites have higher energy of protonation. Parent skeleton (Figure 3) of third set shows that it has four oxygen and single nitrogen atoms. Out of four O-atoms, three (site-2, 13 and 29) act as acceptor, while the rest one (site-21) act as both donor and acceptor. The nitrogen atom of site-4 acts as both acceptor and donor. We have also evaluated energy of protonation of all these sites which are presented in Table 3. A reference to this table shows that the top four favorable hydrogen bond acceptor sites are O29, O13, N4 and O21, as these sites have higher energy of protonation. The –NH– and –CO– groups of amino acids Val-32, Ile-47, Ile-50, and Ile-84 (i.e., receptor protein) are responsible for hydrogen bonding (Scheme 1). The nitrogen atom of the group acts as both hydrogen bond acceptor and donor, while the oxygen atom acts as acceptor only. We have also evaluated energy of protonation of all these sites which are presented in Table 4. A reference to table shows that oxygen atom (―CO―) of both Val and Ile have higher hydrogen bond acceptor (HA) potency than nitrogen atom (―NH―), in other word nitrogen atom (―NH―) of both Val and Ile have higher hydrogen bond donor (HD) potency than oxygen atom (―CO―). Thus, it is the hydrogen of the –NH- group that participates in the H-bond formation with the nitrogen and oxygen atoms of the inhibitor [24]. Ligands that interact by hydrogen bonds can only bind in a certain orientation with its counter parts on receptor protein. Cambridge Structural Database (Scheme 2) provides some parameters to classify the existence, nature and strength of H-bond formed between reacting species. The H-bond properties of very strong, moderate and weak hydrogen bonds are given in Table 4 [25]. Bond length, bond order and bond angle have been used to explain the type, nature and strength of these H-bonds [25]. Bond length, bond order and bond angle have been used to explain the type, nature and strength of these H-bonds [25]. Table 4A1 to 4C4 show the H-bonds properties of the bond formed between the top four HA sites (O25, O15, O13 and N10 of first set, O32, O23, O33 and N10 of second set and O29, O13, N4 and O21 of third set compounds) and HD (H-atom of ―NH― group of Val-32, Ile-47, Ile-50, and Ile-84) site of receptor protein moieties.[20] A close look at the tables (Table 4A1 to 4A4 for first set; Tables 4B1 to 4B4 for second set; and Tables 4C1 to 4C4 for third set) concluded that site-O25, O15 and O13 of all the compounds of first set form moderate H-bonds ranging from 1.833 to 1.883Ǻ with H-atom (―NH―) of Ile moieties of receptor protein, except compound no.-8 which form strong H-bond (1.017Ǻ) with site-O13. All these moderate H-bonds have well defined bond order. The site-N10 form weak H-bond ranging from 3.635 to 5.826Ǻ with H-atom (―NH―) of Val moiety of receptor protein. Compounds no.-7, 12 and 17 forms only three H-bonds and it is the nitrogen atom of site-10, which fails to form H-bond because of low electron density and have small positive charge 0.016, 0.030 and 0.063, respectively. All the weak H-bonds have zero bond order, except compound no.-4, 10 and 13, which have bond order 0.002, 0.002 and 0.003, respectively. Table 4B1 to 4B4 concluded that site-O32, O23 and O33 of all the compounds of the second set also form moderate H-bonds ranging from 1.842 to 1.887Ǻ with H-atom (―NH―) of Ile moieties of receptor protein, except compound no.-23 (site-O23), 26 (site-O32), 29 (site-O23) and 32 (site-O32) which form weak H-bond. All these moderate H-bonds have well defined bond order, except the weak bonds which have zero bond order.

Table 1A
Evaluation of energy of protonation of first set inhibitors
Table 1B
Evaluation of energy of protonation of second set inhibitors
Table 1C
Evaluation of energy of protonation of third set inhibitors
Table 2
Evaluation of energy of protonation of receptor protein
Table 3
Properties of hydrogen bonds
Table 4A1
Calculation of bond properties of H-bond formed between oxygen at site-25 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4A2
Calculation of bond properties of H-bond formed between oxygen at site-15 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4A3
Calculation of bond properties of H-bond formed between oxygen at site-13 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4A4
Calculation of bond properties of H-bond formed between nitrogen at site-10 of the inhibitor and hydrogen of Val moiety of receptor protein
Table 4B1
Calculation of bond properties of H-bond formed between oxygen at site-32 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4B2
Calculation of bond properties of H-bond formed between oxygen at site-23 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4B3
Calculation of bond properties of H-bond formed between oxygen at site-33 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4B4
Calculation of bond properties of H-bond formed between oxygen at site-33 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4C1
Calculation of bond properties of H-bond formed between oxygen at site-29 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4C2
Calculation of bond properties of H-bond formed between oxygen at site-13 of the inhibitor and hydrogen of Ile moiety of receptor protein
Table 4C3
Calculation of bond properties of H-bond formed between nitrogen at site-4 of the inhibitor and hydrogen of Val moiety of receptor protein
Table 4C4
Calculation of bond properties of H-bond formed between oxygen at site-21 of the inhibitor and hydrogen of Ile moiety of receptor protein

The site-N10 forms weak H-bond ranging from 3.395 to 5.613Ǻ with H-atom (―NH―) of Val moiety of receptor protein. Compounds no.-19, 23, 24, 25, 28 and 29 form only three H-bonds and it is the nitrogen atom of site-10 which fails to form H-bond because of low electron density and have small positive charge of 0.006, 0.019, 0.013, 0.027, 0.022 and 0.001, respectively. All the weak H-bonds have zero bond order, except compounds no.-4, 10 and 13, which have bond order 0.002, 0.002 and 0.003, respectively. All these weak H-bonds have zero bond order.

3.2. Non-bonding Interaction

In all previous studies of our research group the donors were organic molecules and acceptors were metal salts [17, 18]. But in this work, both parts of the system under investigation are organic molecules. For this, using absolute electronegativity (χ) [15], firstly each compound has been classified as acid or base with respect to each receptor amino acid and is presented in Table 5.

The intermolecular interaction can be explained by using electron flux. The ∆N represents electron flux and is defined as: ∆N = (χA – χB)/ 2(ηA – ηB), whose negative value represents spontaneous process. In spontaneous process electron will flow from molecule B to A. If two systems under investigation (drug/ inhibitor and receptor/ enzyme) are brought together the electron will flow system of lower χ to that of system of higher χ. And this electron flow will end up by equalization of chemical potential [15b]. It has been established that electronegativity (χ) is the negative of the chemical potential (-μ) [15]. The spontaneous electron flows resulted in lowering of energy of the system [15a]. The lowering of energy of the system is represented by ∆E. Which can be defined as: ∆E = -(χA – χB)2/ 4(ηA – ηB). Herein, ηA and ηB are absolute hardness of the system A and system B. The values of ΔN and ΔE are presented in Table 6. ΔN refracted that binding site on receptor protein has higher values of charge transfer for Val amino acids than Ile amino acids. ΔE shows that binding site on receptor protein has higher value of energy lowering for Val amino acids than Ile amino acids, too.

Table 5
Classification of compounds (acid/A or base/B) with respect to receptor amino acids
Figure 4
HOMO-LUMO Energy Gaps and their change, ∆ELH
Table 6
Calculation of ΔELH, ΔN and ΔE of EI-complexes formed, when HIV-1-PRIs interact with binding site on HIV-1-PR

After that strength of interaction can be studied by using interaction energy, which is represented by ΔEint and defined as ∆Eint = ∆Eν - ∆Eμ [12]. This equation involves two processes one is charge transfer process represent by ∆Eν and other process is reshuffling of charge distribution and is represent by ∆Eμ. Both can be defined respectively as: ΔEv ≈ - (μA – μB)2 SA∙SB / 2(SA + SB) and ΔEμ ≈ -λ/2(SA + SB). Herein, SA and SB are the global softness of system A and system B, respectively [11]. It has been established that global softness (S) is the half of the absolute hardness (½η) [15]. Interaction energy for enzyme-inhibitor interaction between HIV-1-PR and HIV-1-PRIs has been evaluated and is presented in Table 7. ΔEint values show higher values of interaction energy for Ile amino acids than Val amino acids.

Frontier orbitals (HOMO and LUMO) as reported can help to describe intermolecular interaction. This interaction involves HOMO of donor (B) and LUMO of acceptor (A) to come close with same symmetry (Figure 4).

Table 7
Calculation of ΔEv, ΔEμ and ΔEint of EI-complexes formed, when HIV-1-PRIs interact with binding site on HIV-1-PR
Table 8
Calculation of ΔELH, ΔN and ΔE of EI-complexes formed, when HIV-1-PRIs interact with binding site on HIV-1-PR

The energy for such interaction for each complex has been calculated by the equation, ∆ELH = (εLUMO – εHOMO). ∆ELH has been used to measure the weak electrostatic attractions that strengthen the formation of enzyme-inhibitor (EI) complex [13, 14b]. We have calculated eigenvalues of LUMO and HOMO of receptor amino acids and HIV-1-PRIs and placed them in Table 8 Their change ∆ELH have also been evaluated and are also placed in same table. A lower value of this will support strong and effective drug-receptor interaction. ΔELH shows that receptor protein has maximum attraction for Ile amino acids than Val amino acids. As there are three isoleucine residues at positions, 47, 50 and 84 respectively i.e. Ile-47, Ile-50, and Ile-84 and one valine residue at position 32 i.e. Val-32. Results of orbital based study have also been found to supports the results as abstracted from interaction energy.

4. Conclusion

  1. Energy of protonation did good job for correct location of most favorable H-bond acceptor sites. (i) All the compounds of first set form moderate H-bonds ranging from 1.833 to 1.883Ǻ with H-atom (―NH―) of Ile moieties of receptor protein, except compound no.-8 which form strong H-bond (1.017Ǻ) with site-O13. (ii) All the compounds of second set form moderate H-bonds ranging from 1.833 to 1.883Ǻ with H-atom (―NH―) of Ile moieties of receptor protein, except compound no.-8 which form strong H-bond (1.017Ǻ) with site-O13. (iii) All the compounds of the third set form moderate H-bonds ranging from 1.834 to 1.901Ǻ with H-atom (―NH―) of Ile moieties of receptor protein, except compound no.-37 (site-O13), 38 (site-O21), 49 (site-O13), 50 (site-O21) and 51 (site-O21) which form weak H-bond. The site-N4 forms weak H-bond ranging from 3.064 to 5.715Ǻ with H-atom (―NH―) of Val moiety of receptor protein. All these weak H-bonds have zero bond order.
  2. Charge transfer followed by energy lowering reflected maximum interaction with valine amino acids than isoleucine. (ii) While results of interaction energy shows maximum interaction with isoleucine amino acids than valine. (iii) The result of interaction energy is also supported by ΔELH that shows receptor protein has maximum attraction for Ile amino acids than Val amino acids. This may be due to contribution of isoleucine amino acids is much higher (three in number) than the contribution of valine amino acid (one in number).
  3. All the parameters used in this study did good job that judging their selection and can also be used in intermolecular interactions of different nature of compounds.

Acknowledgement

The paper is dedicated to my teacher; mentor, guru father and eminent chemist respected Prof. P.P. Singh (DSc., F.N.A.Sc. and Bharat Shiksha Ratna Awardee) also known as Doctor Sahab. Ex. Principal Maharani Lal Kunwari Post Graduate College, Tulsipur Road, Balrampur-271201 (U.P.), India & Ex. Principal of Bareilly College, Bareilly-243001(U.P.), India. Rajesh Kumar Singh and Vishnu Kumar Sahu gratefully acknowledge the financial support (Project No: C.S.T./D.3564/11/2009) given by “Council of Science & Technology, U.P., INDIA”.

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Sahu, V. K., Chandra, N., Kumar Soni, A., Singh, P., & Kumar Singh, R. (2023). Drug-Receptor Interaction of Peptidic HIV-1 Protease: Intermolecular Interaction-III. Online Journal of Microbiological Research, 3(1), 1–22. Retrieved from https://www.scipublications.com/journal/index.php/ojmr/article/view/630
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