Toward antituberculosis drugs: in silico screening of synthetic compounds against Mycobacterium tuberculosisl,d-transpeptidase 2

Figures & data

Figure 1 (A) 3→3 linkages and (B) 4→3 linkages of the bacterial peptidoglycan layer.

Figure 2 (A) Three-dimensional structure of Ldt_Mt2 protein of Mtb (Ldt_Mt2, PDB ID: 3TUR). (B) Molecular overlay picture of the downloaded Ldt_Mt2 protein structure (green) and prepared Ldt_Mt2 protein structure (pink).

Abbreviations: Ldt_Mt2, l,d-transpeptidase 2; Mtb, Mycobacterium tuberculosis.

Table 1 ADMET and TOPKAT values of meropenem and the top 18 hit compounds

Compound	WOE	AM	DTP	AB	Absorption	Solubility	Hepatotoxicity	CYP2D6 inhibitor	PPB
Meropenem	+	+	+	−	Moderate	Optimal	No	No	<90%
1	−	−	−a	−b	Good	Good	No	No	<90%
2	−	−	−	−b	Good	Good	Yes	No	<90%
3	−	Indb	−a	−b	Good	Good	No	No	>90%
4	+b	−	−a	−b	Good	Good	No	No	<90%
5	−a	−	−	−b	Good	Good	No	Yes	<90%
6	−	−	−	−b	Good	Good	No	No	<90%
7	−	−	−a	−b	Good	Good	No	No	>90%
8	−	−	−a	−	Good	Good	Yes	No	<90%
9	+b	−	−	Indb	Good	Good	Yes	No	<90%
10	−	−	+b	−b	Good	Optimal	No	No	<90%
11	−b	Ind	+b	−b	Good	Low	No	No	<90%
12	−	−	−b	−b	Good	Good	No	No	>90%
13	−	−a	−a	−b	Good	Good	Yes	No	<90%
14	−a	−	−b	−b	Good	Good	No	Yes	<90%
15	+b	−b	−b	−b	Good	Good	No	No	<90%
16	−	−	−a	−b	Good	Good	No	No	<90%
17	−	−	−a	−b	Good	Good	No	No	>90%
18	−	−	−	−b	Good	Good	Yes	No	<90%

Notes: (−): P=0–0.29; Ind: P=0.30–0.69; and (+): P=0.70–1.00. The OPS is a unique multivariate descriptor space in which the model is applicable. Assessment of this is needed to determine if the chemical structure being examined is within a model’s OPS. The probability results may be accepted with confidence, subjected to the results obtained from hypothesis testing.

a Outside of OPS but within OPS limits and

b outside of OPS and OPS limit.

Abbreviations: ADMET, absorption, distribution, metabolism, excretion, and toxicity; TOPKAT, toxicity prediction by komputer assisted technology; WOE, weight of evidence carcinogenicity; AM, Ames mutagenicity; DTP, developmental toxicity potential; AB, aerobic biodegradability; PPB, plasma protein binding; OPS, optimum prediction space.

Figure 3 H37Ra growth inhibition (%) by compound 1 and compound 2 in comparison to the positive control, rifampicin.

Note: Error bars are the standard error of the mean.

Figure 4 H37Ra growth inhibition (%) by compound 2 at 25 μM and 0.2 μM after 24 hours, 48 hours, and 72 hours.

Note: Error bars are the standard error of the mean.

Table 2 2D structures and ligand interactions of meropenem and compound 2 in Ldt_Mt2’s active site

Compound	2D structure	Binding energy (kcal/mol)	van der Waals	Conventional hydrogen bond	Carbon hydrogen bond	Attractive charge	Π–sulfur	Π–alkyl	Alkyl	Π–lone pair	Π–Π T-shaped	Π–sigma	Unfavorable donor–donor
Meropenem (docked)		148.884	Val322,	Trp340,	Thr320,	His336	Trp340,	His352,	His352,	–	–	–	–
			Met303,	Thr320	Arg319,		His336	Trp340	Trp340
			Tyr318,		Cys354,
			His352,		Gly332
			Thr350,
			Ser341,
			Ser351,
			Asn356,
			Lys282,
			Gly353,
			Val333,
			Phe334
Compound 2		164.695	Lys282,	Cys354,	–	–	Trp340,	–		Thr350	His352	Trp340	Lys282
			Thr350,	His336,			His352,
			Arg319,	Asn356,			Cys354
			Ser341,	Trp340,
			Ser351,	His352
			Thr320,
			Tyr318,
			Val322,
			Met303,
			His336,
			Asn356

Notes: Specific amino acids involved for each type of ligand interaction are enumerated for each compound. Calculated binding energies in kilocalorie per mole are also shown.

Abbreviations: 2D, two dimensional; Ldt_Mt2, l,d-transpeptidase 2.

Figure 5 2D ligand interaction diagram of meropenem with Ldt_Mt2’s active site.

Abbreviations: 2D, two dimensional; Ldt_Mt2, l,d-transpeptidase 2.

Figure 6 2D ligand interaction diagram of compound 2 with the Ldt_Mt2 active site.

Abbreviations: 2D, two dimensional; Ldt_Mt2, l,d-transpeptidase 2.